Preparation of synthons and reactions libraries

The database of reactions and corresponding synthons was kindly provided by Enamine (the version of May 2019). All reactions in the database can be separated into two categories: 2-components and 3-component reactions, based on the number of variable synthons. Synthons and reaction libraries were prepared for enumeration using ICM-Pro Molecular Modeling Software³⁵ (Molsoft LLC, San Diego). For each reaction from the reactions database a Markush structure, representing a reaction scaffold with defined attachment points for substituent synthons, was generated in a smile format. Structures of possible synthons for each R-group in each reaction were generated in 2D format with attachment points defined for enumeration. An example of 2-reagents reactions is the one-pot reductive amination of aldehydes with heteroaromatic amines³⁶, as shown in Extended Data Figure 15a. An example of 3-reagent reaction is one-pot formation of thiazoles via asymmetrical thioureas³⁷, shown in Extended Data Figure 15b.